山奈酚药理 文档.doc

对心血管系统疾病电压依赖性K+电流是动作电位复极化早期外向电流，在神经元信号调控中起着重要作用，并且与人类心血管疾病密切相关1。它包括IA和Ik，主要调节静息膜兴奋性，减慢去极化速度，延缓动作电位产生，并可使重复放电神经细胞呈现缓慢放电节律2。脑缺血缺氧时能量消耗加速，从而激活K+通道，使细胞内K+外流增多，胞内能量消耗加速致使Na+-k+-ATP酶活性受到抑制，进一步造成细胞外K+增多，胞内K+减少，Ca2+内流增多，进而诱导细胞凋亡。钾通道阻滞药可以通过减缓神经元胞内能量的消耗，抑制钾通道的激活，减少K+的外流，调节Na+-K+-ATP酶活性及胞内 Ca2+离子的水平，减缓缺血缺氧对神经元造成的损伤3。有研究表明，山奈酚能抑制正常和缺氧时大鼠海马CA1神经元的IA、IK，山奈酚对正常和缺氧时大鼠海马C1A1神经元电压依赖性钾通道有抑制作用，其对钾通道的抑制作用可能参与脑缺血保护4。孙剑寒等5经报告基因实验发现，槲皮素和山奈酚能活化PXR诱导的CYP3A4转录，其中山奈酚的诱导能力最强，而异鼠李素没有类似作用。张芳芳6用原代培养大鼠肝细胞模型，发现山奈酚对红霉素N一脱甲基酶(ENRD)有显著抑制作用，红霉素是肝CYP3A4特异的酶解底物，它在肝中的清除率随年龄增加而降低。徐玫等7等研究表明山奈酚可能抑制动物体内与心血管常用药物钙离子拮抗剂硝苯地平(nifedipine,NFP)作用。Emilio Ruiz8等报道山奈酚抑制由氧化低密度脂蛋白元件引起的血管平滑肌细胞凋亡。1Shich CC.Coghlan M.Sullivan JP.Potassium channels:molecular defects,diseases,and therapeutic opportunities J.Pharmacol Rev.2000,52(1):557.2Xuan Chi X.Xu ZC. Potassium currents in CA1 neurons of rat hippocampus increase shortly after transient cerebral ischemia J. Neurosci Lett.2000,281(1):5.3 Huang H.Gao TM.Gong L.Potassium channcl blocker TEA prevents CA1 hippocampal injury following transicent forebrain ischemia in adult rats J.Neurosci Lett.2001,305(2):83.4董敏，肖亮，宋明柯。山奈酚对急性短暂缺氧时大鼠海马CA1神经元电压依赖性钾通道的作用。中南药学，2004, 6(2),135-138.5 SUN Jian-han, ZHENG Yi-fan, ZHU Hui-Juan, et al(孙剑寒.郑一凡.祝惠娟.等).Genistein,coumestrol and quercetin activate pregnane X receptor-mediated transcription of CYP 3A 4 J.Chinese Journal of Pharmacology and Toxi-cology(中国药理和毒理杂志).2004, 18 ( 3) : 219 -223 (in Chinese)6徐玫等. 山奈酚对大鼠体内硝苯地平药物动力学的影响J.浙江大学学报(医学版)2006,35(1)：23-28.7张芳芳，郑一凡，祝慧娟，等. 山奈酚和榭皮素对大鼠细胞色素P450酶活性的影响J .浙江大学学报:医学版，2006,35(1):18- 22.8Emilio Ruiz, Eugenia Padilla,et al. Kaempferol inhibits apoptosis in vascular smooth muscle induced by a component of oxidized LDLJ. European Journal of Pharmacology.2006 (529): 79-83.抗炎作用槲皮素和山奈酚通过调节诱导型一氧化氮合酶(iNOS)、环氧合酶-2、C反应蛋白，核因子B（NF-B）路径有助于在肝细胞中的抗炎作用，体内机制可能与阻碍核因子B活性1。因为NF- B能通过与相应致炎基因的启动子与增强子结合 ,促进相关基因的转录 ,从而在炎症中起到重要作用2,3。1Victoria Garcia-Mediavilla，Irene Crespo,et al.The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. European Journal of Pharmacology 2007 (557):221-229.2朱则今等.核因子NF-B感在细菌内毒素诱导的实验性角膜基质炎中的表达中国实用眼科杂志第2000,18(11):709-712.3Chang Hwa Jung,Ji Hye Kim,et al.Phenolic-rich fraction from Rhus verniciflua Stokes(RVS)suppress inflammatory response via NF-B and JNK pathway in lipopolysaccharide-induced RAW 264.7 macrophages.Journal of Ethnopharmacology 2007,110:490497.杨秀伟 中药成分代谢分析 第1版 北京:中国医药科技出版社，2003:566-568.抗肿瘤作用山奈酚能在许多类型癌细胞中产生细胞毒素物质，说明具有抗癌潜能1-3。有助于治疗肿瘤坏死因子相关的凋亡诱导配体类癌症4。诱导一系列转化细胞类型的抗肿瘤活性5-7。有抗N-甲基-D-天冬氨酸(NMDA)引起的大鼠皮质神经元的损伤、保护-淀粉样肽引起的成神经细胞瘤细胞(PC12)和乳腺癌细胞(T47D）损伤等作用8-10。山奈酚通过抑制在骨细胞中的肿瘤凋亡因子受体家族，产生极有意义的抗破骨基因效应11。在白血病HL-60细胞中，山奈酚能迅速引起DNA损害，通过有限抑制细胞周期循环，丧失活力12。CK2与淋巴瘤、白血病等血液系统肿瘤关系密切.有研究发现，急性白血病细胞比相应的正常细胞，其CK2活性升高了3-5倍。山奈酚是一种较强的蛋白激酶CK2的抑制剂，揭示山奈酚有抗肿瘤的作用13,14。 1V.Sharma,C.Joseph,S.Ghosh,A.Agarwal, M.K.Mishra,E.Sen, Kaempferolinduces apoptosis in glioblastoma cells through oxidative stress,Mol.Cancer Ther.6(2007)25442553.2C.S.Bestwick,L.Milne,S.J.Duthie,Kaempferol induced inhibition of HL-60 cell growth results from a heterogeneous response,dominated by cell cycle alterations,Chem.Biol.Interact.170(2007)7685.3 H.W.Leung,C.J.Lin,M.J.Hour,W.H.Yang,M.Y.Wang,H.Z.Lee,Kaempferolinduces apoptosis in human lung non-small carcinoma cells accompanied byan induction of antioxidant enzymes,Food Chem.Toxicol.45(2007)20052013. 4Tatsushi Yoshida,et al.Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis J. Biochemical and Biophysical Research Communications,2008 (375)：129133.5P.Niering,G.Michels,W.Watjen,et al,Protective and detrimental effects of kaempferol in rat H4IIE cells:implication of oxidative stress and apoptosis,Toxicol.Appl.Pharmacol.209(2005)114122.6S.Kuntz,U.Wenzel,H.Daniel,Comparative analysis of the effects of flavonoids on proliferation,cytotoxicity and apoptosis in human colon cancer cell lines,Eur J.Nutr.38(1999)133142.7G.Rusak,H.O.Gutzeit,J.L.Muller,Structurally related flavonoids with antioxidative properties differentially affect cell cycle progression and apoptosis of human acute leukemia cells, Nutr.Res.25(2005)143155.8Roth A，SehaflherW，HertelC. Phytoestrogen kaempferol(3，4，5，7-terahydroxy flavone) Protects PCI2 and T47D cells from beta-amyloid-induced toxicity.Neurosci Res，1999，57(3):399-343.9 Sloley BD, Urichuk LJ, Morley P. Identification of kaempferol as a monomine oxidase inhibitor and potential Neuroprotectant in extracts of Ginkgo biloba leaves.Pharm Pharmacol, 2000,52(4): 451-457.10 Dajas F, Rivera-Megre F, Blasina F.Neuroprotection by flavonoids. Braz J Med Biol Res. 2003, 36(12):1613.11Jian L.Pang,Dennis A.Ricupero,et al.Differential activity of kaempferol and quercetin attenuating tumor necrosis factor receptor family signaling in bone cellsJ. bi oc he m i c al ph ar m a co l o g y 2 00 6, 71:818826.12C.S.Bestwick,L.Milne,L.Pirie,S.J.Duthie,The effect of short term kaempferol exposure on reactive oxygen levels